Introduction

The repurposing of drugs is quickly becoming a popular trend in the medical field today. The process decreases time and expenses compared with developing novel therapeutics. Such is the case of Itraconazole. Originally, Itraconazole’s use was to treat fungal infections. But a medical discovery over a decade ago confirmed that Itraconazole has a high-efficiency rate in treating several types of cancers such as lung, prostate, and skin. Therefore, its timely repurposing breathed a new life into the drug. 

This article will provide a comprehensive definition of Itraconazole and how it works. We’ll cover its recommended dosage and proper administration. What’s more, we’ll also talk about clinical facts regarding its efficiency. Finally, we’ll discuss the benefits of using Itraconazole in cancer patients. 

What is Itraconazole?

Antifungal drugs like Itraconazole are medications with antifungal properties. Its initial use is to prevent and treat a wide range of fungal infections like

• Aspergillosis 
• Blastomycosis 
• Candidiasis
• Histoplasmosis

How Does Itraconazole Work in Cancer?

Itraconazole works in treating cancer by inhibiting cellular growth pathways and stopping the formation of new blood vessels. It inhibits the Hedgehog pathway by acting directly on the SMO protein. Smoothened (SMO) is a crucial transmembrane protein in the Hedgehog (HH) signaling pathway. The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell-to-cell interaction and tissue patterning. Mutations in proteins that relay HH signals between cells cause birth defects and cancer.

There are multiple mechanisms of action proposed to explain the diverse anti-cancer effects of itraconazole. These include:

• Antiangiogenic
• Hedgehog pathway inhibition
• Autophagy induction
• Reversal of multidrug resistance
• Angiogenesis

How is Itraconazole Administered?

Oral administration is the typical method of taking Itraconazole. It can also be administered via IV, depending on the case. 

Dosages of Itraconazole

Dosages vary by indication. The usual dosage is 100 mg to 600 mg daily, ranging between one to 30 days. It is also safe  for long-term maintenance for prophylaxis. For example, 200 mg to 400 mg daily for HIV-infected patients. And 400 mg daily for patients suffering from chronic pulmonary aspergillosis. In clinical trials for cancer patients, the dose of itraconazole can be 600 mg daily. 

Itraconazole Uses Reminders:

• Always take Itraconazole after meals. 
• Avoid chewing or breaking the Itraconazole tablets or capsules

How Efficient is Itraconazole?

Early pre-clinical investigation of the anti-cancer potential of itraconazole  focused on a potential role as a potentiator for chemotherapeutic drugs. Mainly as a possible agent to reverse multidrug resistance (MDR).

• Itraconazole had potent antiangiogenic activity.
• Itraconazole is a Hedgehog pathway inhibitor at a clinically relevant concentration of 800 nM.  

Case Studies Reporting the Efficiency of Itraconazole in Cancer Treatment

A 65-year old patient with biochemically recurrent prostate cancer who is unwilling to undergo castrating treatment received a high dose of itraconazole (300 mg b.i.d.). A significant >50% reduction of PSA level after 12 weeks with no significant change in testosterone level. The 50% decrease in PSA levels was maintained during itraconazole treatment but increased after itraconazole discontinuation.

Here’s another report detailing a case of pancreatic cancer that showed a response to itraconazole treatment. The patient was a heavily pre-treated 64-year- old male with unresectable stage III pancreatic adenocarcinoma. He developed disseminated histoplasmosis following his third cycle of gemcitabine.  He underwent itraconazole for nine months without concurrent chemotherapy or other treatment. His pancreatic cancer was reassessed and found to be resectable. After four years following the successful surgical resection, he showed no recurrence or metastatic disease signs.

Lastly, a pilot trial of itraconazole pharmacokinetics in patients with metastatic breast cancer has also reported results. Patients (n = 14) received oral itraconazole at a 200 mg dose per day until reaching disease progression or unacceptable toxicity.  Outcomes: The pharmacokinetic data (plasma levels of itraconazole and hydroxyitraconazole) correlated with measures of angiogenesis—plasma VEGF-A and thrombospondin -1 (TSP-1), serum basic fibroblast growth factor (bFGF), and placental growth factor PlGF—at baseline, two and four weeks. 

The evidence above suggests that itraconazole has many anti-cancer effects at clinically achievable doses. There is evidence that it may also apply to many other cancers, including glioblastoma, breast, and ovarian.

Possible Side-Effects of Itraconazole

The most common side effects of Itraconazole are 

• Nausea 
• Abdominal pain 
• Rash

The less common side effects include

• Gastrointestinal upsets (vomiting, flatulence, diarrhea, and constipation)
• Headache 
• Dizziness
• Peripheral neuropathy

Rare but severe side effects 

• Liver failure
• Chronic heart failure
• Neutropenia

Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4, and there is an extensive list concerning drug interactions. Keep in mind that Itraconazole increases the severity of neurotoxicity associated with vincristine. Be mindful of the Itraconazole drug-drug interactions. 

Conclusion

It would be interesting to combine itraconazole with a range of other drugs, including, but not limited to, cytotoxic chemotherapies. The pre-clinical and clinical data with platinum-based chemotherapies and the clinical data with pemetrexed are pretty promising. 

Conceptually, combinations with drugs that target other points in the Hedgehog pathway, or with drugs that target different mechanisms of stem cell survival, or with drugs targeting non-stem cells all make eminent sense. 

The evidence for an anti-cancer effect of itraconazole treatment comes from in vitro, in vivo, and human data. It has well-established pharmacokinetics and a known toxicity profile making this generic drug a strong candidate for repurposing. It is best to combine existing standard of care treatments and other repurposed drugs as oncological treatments. 

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Dr. Paul Zhang is one of the most-sought after oncologists specializing in integrative cancer care and off label medicine uses. He has a proven track record of evidence-based treatments for a wide range of cancers. Call today for more information. Dial 713-797-1900.